Deamino derivatives of the kallikrein-trypsin inhibitor

Abstract

A demaino kallikrein-trypsin inhibitor obtained from cattle organs is characterized by (a) 0 to 3 lysine residues and/or 3 to 6 arginine residues and/or 1 to 4 tyrosine residues; (b) the 10- and/or 21-tyrosine residues being unsubstituted or substituted by at least one nitro, nitroso or amino in the ortho position relative to the phenolic hydroxy group; and (c) having protease inhibitory activity of BPTI and elastase inhibition activity.

What is claimed is: 
     
       1. A process for the preparation of a deamino kallikrein-trypsin inhibitor obtained from cattle organs which comprises reacting (a) a nitro derivative of BPTI or a deamido derivative of BPTI at a pH of from about 2 up to about 7 with a compound which supplies nitrous acid or nitrosyl ions at a temperature of from about -20° C. to about +30° C. and in the presence of an acid, or   (b) reacting BPTI, a nitro derivative of BPTI or a deamido derivative of BPTI at a pH of from about 1 to about 12 with a diazonium compound at a temperature of from about -20° to about +30° C.   
     
     
       2. A process according to claim 1, wherein reaction (a) is carried out in the presence of a nucleophilic reagent. 
     
     
       3. A process according to claim 1, wherein reaction (b) is carried out under an inert gas or under vacuum. 
     
     
       4. A process according to claim 1, wherein the reaction (a) is carried out in an aqueous solution which contains an organic solvent. 
     
     
       5. A process according to claim 1, wherein compounds obtained from reaction (a) or (b) are treated to reduce any occurring nitro nitroso groups. 
     
     
       6. A process according to claim 1, wherein the reaction product is fractionated. 
     
     
       7. A process according to claim 1, wherein the compound supplying nitrous acid or nitrosyl ions is selected from the group consisting of salts of nitrous acid, nitrosylchloride, nitrosylsulphuric acid, and alkyl esters of nitrous acid. 
     
     
       8. A process according to claim 1, wherein the diazonium compound is a diazotised heterocyclic amine. 
     
     
       9. A pharmaceutical composition useful in the treatment of diseases caused by overproduction of proteases, comprising a therapeutically or prophylactically effective amount of the deamino kallikrein-trypsin inhibitor obtained from cattle organs having elastace inhibition activity, characterized by (a) 0 to 3 lysine residues and/or 3 to 6 arginine residues and/or 1 to 4 tyrosine residues; and   (b) the 10- and/or 21-tyrosine residues being unsubstituted or substituted by at least one nitro, nitroso or amino in the ortho position relative to the phenolic hydroxy group, in combination with a pharmaceutically acceptable solid or liquid inert carrier or diluent therefor.   
     
     
       10. A composition according to claim 9, in the form of a sterile and isotonic aqueous solution. 
     
     
       11. A composition according to claim 9 containing from about 0.5 to about 95% by weight of the said deamino derivative. 
     
     
       12. A method of treating diseases caused by overproduction of proteases, which comprises administering to the host in need thereof a therapeutically or prophylactically effective amount of the deamino kallikrein-trypsin inhibitor obtained from cattle organs having elastace inhibition activity, characterized by (a) 0 to 3 lysine residues and/or 3 to 6 arginine residues and/or 1 to 4 tyrosine residues; and   (b) the 10- and/or 21-tyrosine residues being unsubstituted or substituted by at least one nitro, nitroso or amino in the ortho position relative to the phenolic hydroxy group.   
     
     
       13. A method according to claim 12, in which the deamino derivative is administered in an amount of from about 0.1 to about 20 mg per kg body weight per day. 
     
     
       14. A method according to claim 12, in which the deamino compound is administered parenterally, topically or orally.